Signaling pathways regulating VDAC1 overexpression associated with apoptosis, pyroptosis, and ferroptosis.

Mitochondrial VDAC1 is a multi-functional protein that acts as a convergence point for various cell survival and death signals. Under stress and pathological conditions, VDAC1 is overexpressed. This leads to its oligomerization, which forms a large channel allowing pro-apoptotic proteins release and subsequent apoptosis. Here, we studied the signaling pathways regulating VDAC1 overexpression. We show that various agents, inducing programmed cell death (PCD), including apoptosis, ferroptosis, or pyroptosis, also increased VDAC1 expression levels and its oligomerization. Activation of p38-MAPK, c-Jun, N-terminal kinase (JNK), and calmodulin kinase-II signaling pathways by PCD inducers resulted in phosphorylation of the transcription factors (TFs) c-Jun, c-Fos, and ATF-1, and enhanced VDAC1 expression. Consequently, inhibiting these pathways using specific inhibitors decreased VDAC1 expression at the protein and mRNA levels and PCD. Similar results were obtained using a reporter gene approach—the VDAC1-promoter-luciferase construct—in which the activation of apoptosis resulted in the transcription of luciferase that was reduced by signaling pathway inhibitors. These results suggest that the VDAC1 promoter is regulated by the p38-MAPK, JNK, and calmodulin-dependent kinase-II signaling pathways via activation of the TFs c-Jun, c-Fos, and ATF-1 and required Ca2+. These three TFs, upon their activation by cisplatin, bind to the VDAC1 promoter, as demonstrated by a ChIP assay. Thus, VDAC1 promoter regulation represents a potential therapeutic for targeting diseases associated with VDAC1 overexpression.